Ethics, Medicine and Public Health (2016) 2, 362—371

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DOSSIER ‘‘ETHICS, MEDICINE AND GENETICS’’ /Studies

Informed decision-making about prenatal

cfDNA screening: An assessment of
written materials
La prise de décisions éclairée sur le dépistage prénatal cfDNA : une
évaluation des documents écrits
a,∗ b c,1 a
M. Michie , S.A. Kraft , M.A. Minear , R.R. Ryan ,
d
M.A. Allyse
a
Institute for Health & Aging, University of California, 3333 St. Suite 340, CA 941118-
0646 San Francisco, California, San Francisco
b
Stanford Center for Biomedical Ethics, Stanford University, Stanford, United
c
States Science and Society, Duke University, Durham, NC, United States
d
Biomedical Ethics Program, Mayo Clinic, Rochester, MN, United States

Received 22 March 2016; accepted 22 May 2016

Available online 13 September 2016

KEYWORDS Summary
cfDNA; Objectives. — The introduction of prenatal cfDNA screening for fetal aneuploidy and other
NIPT; genetic conditions has exacerbated concerns about informed decision-making in clinical
Prenatal screening; prena-tal testing. To assess the information provided to patients to facilitate decisions about
Informed consent; cfDNA screening, we collected written patient education and consent documents created by
Reproductive health labora-tories and clinics.
Methods. — Informed consent documents (IC) were coded by two independent coders. Each
IC was assessed for readability, attention to elements of informed consent, and completeness
of information about the test and the screened conditions.
Results. — We found variance between IC produced by commercial laboratories versus those
provided by local clinics or health care systems, and considerable variance among materials from
all sources. ‘‘Commercial’’ IC were longer and written at a more difficult reading level than ‘‘non-
commercial’’ IC, and were less likely to state explicitly that cfDNA only screens for

∗
Corresponding author.
E-mail address: marsha.michie@ucsf.edu (M. Michie).
1
MAM is currently serving as an AAAS Science & Technology Policy Fellow at the National Institutes of Health. She contributed to this
article in her personal capacity. The views expressed are her own and do not necessarily represent the views of the National Institutes of
Health, the Department of Health and Human Services, or the United States government.

http://dx.doi.org/10.1016/j.jemep.2016.05.004
2352-5525/© 2016 Elsevier Masson SAS. All rights reserved.
Informed decision-making about prenatal cfDNA screening 363

certain conditions. About one-third of IC were combined with laboratory order forms. Though
most IC recommended confirmatory testing for positive results, only about half clearly stated
that results could be incorrect —– including mentions of false positives or false negatives.
About one-third of IC explicitly stated that cfDNA screening was optional. While nearly all IC
from any source listed the conditions screened by the test, only about half of the IC included
any phenotypic descriptions of these conditions. Few IC mentioned psychosocial
considerations, and only one IC mentioned the availability of support groups for families of
children with genetic conditions.
Conclusions. — Based on our findings, we recommend that written and well-informed consent
be sought before performing cfDNA screening, and we offer minimal and recommended
standards for patient education and consent materials.
© 2016 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé

cfDNA ; Objectifs. — L’introduction du dépistage prénatal cfDNA aneuploïdie fœtale et d’autres mal-adies
NIPT ; génétiques a exacerbé des préoccupations au sujet de prise de décisions éclairée dans les cliniques
Dépistage prénatal ; de dépistage prénatal. Afin d’évaluer les informations fournies aux patients pour faciliter les
Consentement décisions sur le dépistage de la cfDNA, nous avons recueilli la documentation aux patients et les
consentements écrits émanant des laboratoires et des cliniques.
éclairé ;
Méthodes. — Les documents de consentement éclairé (IC) ont été codés par deux programmeurs
Médecine de la
indépendants. Chaque IC a été évalué pour sa lisibilité, pour les éléments du consentement éclairé
reproduction
et l’exhaustivité des informations sur le test et les conditions de dépistage.
Résultats. — Nous avons trouvé des différences entre les IC produits par les laboratoires com-
merciaux par rapport à ceux fournis par les cliniques locales ou des systèmes de soins de santé et
une variance considérable entre les matériaux de toutes les sources. Les IC « Commerciaux »
étaient plus longs et rédigés à un niveau de lecture plus difficile que les IC « non commerci-aux »
et étaient moins susceptible de statuer explicitement sur le statut de dépistage du cfDNA
seulement sous certaines conditions. Environ un tiers des IC ont été combinés avec les bons de
commande de laboratoire. Si la plupart des IC recommandaient des tests de confirmation pour des
résultats sûrs, seulement environ la moitié a clairement indiqué que les résultats pourraient être
incorrects —– en incluant les mentions de faux positifs ou faux négatifs. Environ un tiers des IC a
explicitement déclaré que le dépistage cfDNA était facultatif. Tandis que presque tous les IC de
n’importe quelle source répertoriaient les conditions examinées par le test, seule-ment environ la
moitié des IC incluait une description phénotypique de ces conditions. Peu d’IC ont mentionné les
facteurs psychosociaux et seul un IC a mentionné l’existence de groupes de soutien pour les
familles des enfants atteints de maladies génétiques.
Conclusions. — D’après nos résultats, nous recommandons que le consentement écrit et bien
informé soit fourni avant d’effectuer le dépistage des cfDNA, et nous offrons des normes
mini-males de recommandation pour l’éducation du patient et les éléments du
consentement. Une de nos neuf recommandations est que quelle que soit la question de
savoir si une signature est requise, les documents de consentement éclairé devraient inclure
une instruction simple suggérant de ne pas associer des accords juridiques ou financiers. Le
nom et les coordonnées d’une clinique locale disponible pour d’autres questions devraient
également figurer en bonne place.
© 2016 Elsevier Masson SAS. Tous droits reserv´es´.

Introduction availability, now virtually worldwide; and in scope of clin-ical

Prenatal genetic screening using cell-free DNA (cfDNA)
became commercially available for clinical use in late 2011.
Often called non-invasive prenatal testing or screening (NIPT
or NIPS), cfDNA screening has expanded rapidly: in num-bers
of conditions screened by each assay; in geographic
practice, now potentially offered for any pregnancy regardless
of a priori risk for fetal conditions [1—3]. The increasing
popularity of cfDNA screening has been propelled, at least in
part, by its advantages over previously available screening
and diagnostic testing: it requires only a mater-nal blood
sample; it can theoretically be performed earlier
364
in gestation; and, for certain genetic conditions, it is more
accurate than previous screens [4]. However, the introduc-
tion and rapid adoption of prenatal cfDNA screening has
exacerbated concerns about informed decision-making for
clinical prenatal testing. These concerns include the influ-
ence of aggressive commercial marketing and media hype
about cfDNA screening, the increasing amount of informa-tion
that pregnant women/couples are expected to absorb during
the prenatal period, and the routinization of genetic testing
in prenatal care, especially in light of the minimal procedural
risk involved in cfDNA screening [5,6].
It is tempting to think of cfDNA screening, much like more
standard serum screens, as a test for which written informed
consent is unnecessary; indeed, some health care providers
consider written consent less important for cfDNA screening
than for diagnostic testing such as amniocentesis [7].
However, as cfDNA screening expands, it forces women and
families to confront ever more challenging deliberations
about whether to have prenatal testing and how to deal with
test results [8—10]. Because of the ease of a blood draw and
the early gestational stage at which it is often performed,
many patients may lack not only understanding of the pur-
pose of cfDNA screening, but also awareness that it may lead
to difficult decisions about pregnancy management, invasive
testing, family quality of life, and pregnancy termination
[8,11—14].
Due to these concerns, ethicists have recommended that
informed decision-making practices for cfDNA screening
should resemble those for prenatal diagnostic testing
[12,15,16]. As the scope of cfDNA screening continues to
expand [1,3,17], the informational load of testing on patients
will continue to rise, along with the possibility that patients
and families will make pregnancy decisions based on
inadequate information about test results, test limita-tions,
and screened conditions [6,18—20]. However, with multiple
competing companies offering cfDNA screening and few
standards for educating patients and guiding informed
decision-making, it is not clear what information patients are
utilizing to make cfDNA screening decisions. In order to better
understand the information guiding patient deci-sions, we
evaluated written informed consent documents for cfDNA
screening, and have provided recommendations to improve
the informed consent process.
Background
Informed consent for a health care decision requires a com-
petent individual to voluntarily and intentionally, without
substantial external control, authorize a professional to
perform a plan or procedure [21,22]. An informed choice is
based on adequate and high-quality information, allows
individuals to weigh multiple options, and reflects the
decision-maker’s values [23,24]. A 1982 report from the US
President’s Commission for the Study of Ethical Prob-lems in
Medicine and Biomedical and Behavioral Research concluded
that an informed decision-maker must have sub-stantial
relevant knowledge and understanding of the health care
intervention in question (including the indications for the
intervention, available alternatives, possible risks and
benefits, possible costs and consequences, and signif-icant
uncertainties about any of this information) and is
M. Michie et al.
fundamentally entitled to accept or reject it [25].
Although the normalization of consent practices in health
care has often resulted in legalistic documents that
protect the interests of institutions, the ethical imperative
of informed consent is a process of conversation and
consideration, rather than a single signed document, and
ideally nurtures patient well-being, empowerment, and
trust [21,26]. How-ever, written information often helps
patients assimilate information at their own pace, and
signing a document may provide them an opportunity to
reflect upon and exercise their free choice [8,25,26].
Several professional clinical societies have issued recom-
mendations for the implementation of cfDNA screening, and
all include mention of informed decision-making [27—30]. All
of these recommendations agree that cfDNA screening is a
high-quality screening test for certain fetal aneuploi-dies,
particularly in populations at elevated risk for those
conditions; that when cfDNA is offered, patients should be
counseled with information about the test and its benefits and
limitations; and that positive results should be followed up
with genetic counseling and confirmed with diagnostic
testing. Though early recommendations endorsed the offer of
cfDNA screening only in cases of elevated risk for aneuplo-idy,
more recent studies have validated cfDNA screening in
average-risk populations, and the most recent professional
recommendations have recognized cfDNA screening as a per-
missible option for the general obstetric population, though
not as a standard first-tier screen [29—31]. As of 2016, no
professional society has made specific recommendations for
written informed consent documents. However, in 2012, All-
yse and colleagues developed a set of ethical best practices
for the provision of cfDNA screening, which recommended
that after pre-test counseling, patients should review and sign
a documentation of their consent or refusal, and that this
document should include:
• a list of indicated tests that patients may choose to
undergo;
• a description of all possible findings and their validity
(including the potential for assay failure), utility, and
lim-itations;
• a list of alternative tests for similar indications if appli-
cable;
• and options for patients who do not wish to receive all
results [15].
More recently, the European and American Societies of
Human Genetics (ESHG and ASHG, respectively) issued a joint
policy statement on ‘‘responsible innovation’’ in cfDNA
screening, echoing the need to avoid routinization and
facilitate informed decision-making with counseling and
education, and calling special attention to the needs of
patients whose language, culture, or health literacy may
differ from those of the clinician or majority population [16].
In the context of cfDNA screening, fully informed con-sent
requires at least some knowledge of the conditions being
screened, which ideally includes some idea of the range of
clinical phenotypes and the quality of life that affected
individuals and their families may expect [15]. The
information parents are offered about genetic conditions
should be up-to-date, accurate, and balanced — – particu-
larly because potential parents make termination decisions
against a backdrop of consistent societal bias against those
Informed decision-making about prenatal cfDNA screening
with disabilities [32—34]. Evidence suggests that cfDNA
screening could lead to increased pregnancy terminations
[35,36]; indeed, nearly 15% of surveyed genetic counselors
indicated they had at least one patient terminate a preg-
nancy in their clinic based on cfDNA screening results alone
[37]. Bias concerning disability, both among health care
providers and in public opinion, may influence such decisions
[38—41]. However, assumptions about the costs, limitations,
and suffering associated with disability often do not reflect
the experiences of those living with disability. For example, a
US study found that most mothers of children with Down
syndrome reported high overall family functioning [42]; and a
UK study of individuals living with Down syndrome found that
they viewed their lives as rewarding and attributed problems
less often to their genetic condition than to social barriers,
such as a lack of opportunities and income [43]. The wide
variability of phenotypes within and among conditions that
may be detected with cfDNA screening means that few
patients will know precisely what to expect when a partic-ular
condition is detected, and that informed decisions will require
the availability of balanced, family-relevant infor-mation
about these conditions.
The need for adequate patient education and informed
decision-making support is pressing, given the rapid inte-
gration of cfDNA screening into prenatal care and a strong
preference for noninvasive prenatal testing. US studies have
found strong support among pregnant women and the gen-eral
public for cfDNA screening, emphasizing that they value its
noninvasiveness, accuracy, early timing, testing ease, and the
ability to determine fetal sex [8,44]. However, research has
shown that women’s choices in prenatal screening are strongly
influenced by the attitudes of health care providers and the
way screening is described by both providers and
informational pamphlets [22]. And a recent study found that
patient educational materials from US laboratories offer-ing
cfDNA screening had high reading levels and were not
congruent with content recommendations from professional
organizations [45]. The present study examines informed
consent documents for cfDNA screening from a variety of
sources, assessing the components of information provided
and offering recommendations for improving the consent
process.
Methods
Informed consent documents (IC) were collected between
March and December of 2014. Documents were collected
through professional contacts with individual clinics or cli-
nicians (n = 21), through Internet searches (n = 69), and
via a request posted to an email list for prenatal genetic
coun-selors (n = 3). Dates on documents, when available,
ranged from 2012 (no month identified) to October 2014.
Documents were included if they were in English (or were
multilingual including English), and either:
• included a consent statement for cfDNA screening with
a signature line;
• or were otherwise clearly identified as patient informa-
tion sheets for cfDNA screening.
Advertising brochures from laboratories were excluded
unless they also included a patient consent statement with
365
a signature line. Documents were excluded from the final
coding set if they did not meet the inclusion criteria
above, or if they substantially duplicated another
document in the coding set.
Four of the authors collaboratively developed a code-book,
then iteratively refined it by successively coding two test
documents independently and editing the codebook by
consensus after each test coding. One author and another
independent coder coded all documents using this code-book.
Most information was coded as either present or absent
(yes/no). Information about screened conditions was coded 0
if absent; 1 if the condition was mentioned but not described;
and 2 if the condition was described, includ-ing phenotype.
When documents contained information that was not directed
to patients (e.g., laboratory order forms), only the portion of
the document directed to the patient was coded. Results from
the two coders were compared using either Cohen’s kappa
(for yes/no codes) or weighted kappa (for codes with 3
options). Codes with kappas of 0.6 or below were re-coded
after re-training on the meaning of the code. Three codes had
an unusually low kappa (≤ 0) despite near-unanimous
agreement, due to a well-known paradox in Cohen’s kappa;
the discrepancies in these two codes were reconciled
manually by the two coders and removed from the final kappa
average. Final kappas averaged 0.84, with a range of 0.61—
1.00. Any remaining discrepancies were then manually
reconciled by a third coder to achieve final coding decisions
for each document. Flesch-Kincaid read-ing grade level (to
estimate reading difficulty) was also assessed, by pasting
document content (minus headers, footers, and content not
directed to the patient) into the website:
http://www.readability-score.com.
Results
Sample
We collected a total of 93 informed consent documents
(IC). Of these, 61 were discarded because they were
duplicates or because, upon review, they did not meet the
inclusion criteria. The final coding set thus consisted of 32
IC (Table 1). About half (n = 15) were from the US, and the
rest were from 10 other countries (Fig. 1).
Figure 1. Source of final coding set IC by country.
Source du codage final par pays.
366
Table 1 Informed consent documents (IC).
Documents de consentement éclairé.
IC solicited from IC collected from
professional Internet searches
contacts
Initial sample 21 69
Final coding set 5 24
Commercial vs. Non-Commercial IC
We categorized 22 documents as ‘‘Commercial IC’’ (pro-
duced by a commercial laboratory for broad distribution)
and 10 as ‘‘Non-Commercial IC’’ (produced by a local
clinic or health care system for their own patients) (Table
2). Commercial IC were typically longer and written at a
more difficult reading level than Non-Commercial IC;
these readability differences are partially due to the fact
that Commercial IC often included legal disclosures and
financial responsibility statements, which were sometimes
lengthy and complex. For example, Commercial IC often
devoted space to information about laboratory
certification and/or about sample retention and use,
which is regulated in some jurisdictions. Commercial IC
more often cited the high sensitivity of cfDNA screening,
particularly for tri-somy 21 (Down syndrome); however,
Commercial IC also much more often listed limitations on
the use of cfDNA screening (most often limitations on
multiple gestations), and more often noted that cfDNA is
optional and that post-test genetic counseling is an
option. Non-Commercial IC more often stated the cost of
cfDNA screening and men-tioned the possibility of assay
failure —– which can occur when the sample does not
contain sufficient DNA from the fetus or placenta, or for
other reasons that are not fully understood.
IC format
About one-third of IC (n = 11) were combined with a labora-
tory order form. This format occurred in both Commercial IC
and Non-Commercial IC. The format varied, but typi-cally
consisted of a single document with a laboratory order form
—– including a brief patient consent to be signed —– on the
front, and more detailed patient information on the back.
Two of these 11 forms did not include any detailed patient
information; in both cases, however, the patient was directed
to sign an acknowledgement that she had received
information about the test from her provider —– suggest-ing
that these forms were intended to be distributed with
accompanying materials. The IC that were combined with
laboratory order forms often crowded a great deal of infor-
mation into one document, and portions directed at the
patient were sometimes interspersed with instructions for
clinicians ordering the test. Thus, it was frequently unclear
whether patients were given a copy of this information to
take home. Among all IC, the patient was specifically directed
to keep a copy of the IC in only two cases (one IC that was
combined with a laboratory order form, and one that was
not).
M. Michie et al.
IC solicited from Total IC
genetic counseling
online mailing list
3 93
3 32
Information about test capabilities,
results, limitations, and complications
Professional guidelines all confirm that cfDNA is a
screening test that is not diagnostic. The phrases ‘‘not
diagnostic’’ and ‘‘screen’’/‘‘screening test’’ appeared in
15 and 19 IC, respectively (Table 3). About one-third of IC
(n = 10) men-tioned alternative tests (including diagnostic
tests), and only half of these gave any description of these
alternatives. As noted above, most IC mentioned that
there are circum-stances when cfDNA screening cannot be
performed, which (depending on the specific test) can
include multiple gesta-tions, pregnancies from in vitro
fertilization, consanguinity, prior bone marrow transplants
in the mother, and certain parental genetic anomalies.
Most IC (n = 24) also noted the gestational age when cfDNA
screening could be offered, usu-ally 9 or 10 weeks.
The format of test results from cfDNA screening varies,
with some tests returning a risk score and others retur-ning
simpler results such as ‘‘Aneuploidy (not) detected.’’ A
majority of IC (n = 19) mentioned the format in which test
results would be delivered, and half (n = 16) stated the per-
son to whom test results are returned (usually the health care
provider). Most IC (n = 28) recommended confirmatory testing
for positive results, though fewer (n = 23) clearly stated that
results could be incorrect, including mentions of false
positives or false negatives (Table 3).
Specific numbers for either test sensitivity or specificity
were mentioned in over one-third of IC (n = 13); however,
no IC offered information on the positive or negative
predictive values (PPV or NPV) of cfDNA screening, either
explicitly by these names or in a lay explanation. A few IC
(n = 4) men-tioned that testing could uncover incidental
genetic findings about a parent, and none indicated
whether this informa-tion would be reported to the
patient. No IC mentioned that testing may reveal tumors
or cancer in the mother (Table 3).
Information about screened conditions
Conditions screened by cfDNA vary; while all the tests rep-
resented by our sample screened for trisomies 21, 18, and 13,
some tests screened for many more —– including fetal sex, sex
chromosome aneuploidies, and select microdeletion
syndromes —– and these additional results were sometimes
available only on an opt-in basis, and/or at extra cost. In our
sample only one IC did not include any mention of screened
conditions. However, while nearly all IC listed the conditions
screened, only about half (n = 17) included any phenotypic
descriptions of any of the conditions, and
Informed decision-making about prenatal cfDNA screening 367

Table 2 Commercial IC versus Non-Commercial IC.

Consentement éclairé commercial vs non-commercial.
Commercial IC (n = 22) Non-Commercial IC (n = 10) All IC (n = 32)
Median word count (Range) 944 (214—2132) 540 (361—1567) 814 (214—2132)
Median Flesch-Kincaid reading grade 12.0 (8.9—13.8) 10.6 (8.6—11.7) 11.5 (8.6—13.8)
level (Range)
Mentioned regulatory approval of 13 (59) 0 (0) 13 (41)
laboratory facilities, n (%)
Mentioned or discussed sample retention 19 (86) 1 (10) 20 (63)
or use, n (%)
Cited the sensitivity of cfDNA screening 10 (46) 3 (30) 13 (41)
for any condition, n (%)
Mentioned limitations on cfDNA screening 17 (77) 3 (30) 20 (63)
(e.g., multiple gestations, bone
marrow transplant recipients), n (%)
Clearly stated that cfDNA screening is 10 (46) 3 (30) 13 (41)
optional, or that patient can refuse, n
(%)
Mentioned the option of post-test genetic 15 (68) 4 (40) 19 (59)
counseling, n (%)
Stated the cost of cfDNA screening, n (%) 1(5) 4 (40) 5(16)
Mentioned the possibility of assay failure, 12 (55) 7 (70) 19 (59)
n (%)

Table 3 Information about test capabilities, results, and screened conditions.

Informations sur les capacités du test, des résultats et des conditions du dépistage.
Number (%)
Total n = 32
Used the phrase ‘‘not diagnostic’’ to describe cfDNA screening 15 (47)
Used the phrase ‘‘screen’’ or ‘‘screening test’’ to describe cfDNA screening 19 (59)
Used ‘‘not diagnostic’’ AND/OR ‘‘screen’’ phrases 25 (78)
Mentioned alternative tests (including screening and diagnostic testing) 10 (31)
Described alternative tests (including screening and diagnostic testing) 5(16)
Noted gestational age when cfDNA screening can be offered 24 (75)
Mentioned format of test results (e.g., risk score or ‘‘Aneuploidy detected’’) 19 (59)
Stated person to whom test results are returned 16 (50)
Recommended confirmatory diagnosis for screen-positive results 28 (88)
Noted that results can be incorrect (including false positives/negatives) 23 (72)
Test sensitivity listed 13 (41)
Test specificity listed 8(25)
Positive predictive value (PPV) listed 0(0)
Negative predictive value (NPV) listed 0(0)
Mentioned that cfDNA can reveal genetic anomalies in a parent 4(13)
Mentioned that cfDNA can reveal tumors or cancer in the mother 0(0)
Listed at least one screened condition 31 (97)
Included phenotypic description of trisomies 21, 18, and/or 13 17 (53)
Included phenotypic description of any other condition 9(28)

very few included any contextual information about qual-
ity of life (Table 3). Phenotypic descriptions, when they
did appear, were usually very brief, general, and
symptom-focused. For example, an IC for the verifi TM test
included this description:
Trisomy 21, trisomy 18, and trisomy 13 are three of
the most commonly occurring trisomies seen in babies
at birth. Although the outcomes are variable, these
conditions can cause mild to severe intellectual
disabili-ties, and can cause multiple physical problems
including congenital heart defects, defects in other
organs, and a shortened life span.
An IC from the Oregon Health Authority included this
description of the same conditions:
• Down syndrome: children with Down syndrome have a
wide spectrum of physical and cognitive disabilities;
368
Table 4 Information about counseling, psychosocial issues, and other considerations.
Informations sur le conseil, les questions psychosociales et autres considérations.
Directed patients to think about or discuss questions prior to screening
Mentioned availability of pre-test counseling
Mentioned cost (if any) of genetic counseling
Noted that prenatal screening can cause anxiety
Noted that results may lead to decision-making about termination
Listed any support groups for families with a genetic condition
Mentioned that patient is responsible for cost of cfDNA screening
Stated the cost of cfDNA screening
Described test procedures involving the patient
Disclosed that pregnancy outcomes may be shared with the laboratory
Mentioned regulatory oversight of cfDNA screening
• Trisomy 18: children with trisomy 18 have significant
phys-ical and cognitive disabilities. Their life
expectancy is shortened;
• Trisomy 13: children with trisomy 13 have significant
phys-ical and cognitive disabilities. Their life
expectancy is shortened.
While both documents included a web address for fur-
ther information, these descriptions by themselves offer
minimal phenotypic information. For other aneuploidies
and microdeletion syndromes, phenotypic descriptions
were even rarer.
A few IC did include more detailed information, includ-
ing information about quality of life for children born with
a screened condition. A patient information booklet from
Intermountain Healthcare included this description of
Turner syndrome (45, X):
Girls with Turner syndrome may be born with heart
defects requiring surgery, and generally, they are short
compared to their family members. They may have
learning disabilities, but most girls with Turner syndrome
have normal intelligence. When a woman is pregnant with
a girl with Turner syndrome, the pregnancy has a very
high chance of ending in miscarriage.
A description of Turner syndrome from an IC for the
PanoramaTM test included this information:
Girls with Monosomy X are shorter than average. Some
girls have heart or kidney defects, hearing problems,
and some have minor learning disabilities. Girls with
Mono-somy X may need growth hormone treatments in
early childhood and usually need sex hormone
treatments at the time of puberty. As adults, they
often have infertil-ity.
This level of detail about potential phenotypes for
screened conditions was uncommon in the sample.
Information about test counseling
and psychosocial issues
Most IC (n = 23) noted that patients should think about or dis-
cuss any questions prior to deciding about cfDNA screening,
M. Michie et al.
Number (%)
Total n = 32
23 (72)
15 (47)
0(0)
2(6)
2(6)
1(3)
13 (41)
5(16)
18 (56)
9(28)
3(9)
and many of these (n = 15) specifically mentioned pre-test
genetic counseling (Table 4). For example, an IC for the
TM
Harmony test noted, ‘‘Talk to your healthcare provider
before you decide if the Harmony Prenatal Test is appro-
priate for you,’’ and just before the patient signature line
stated, ‘‘I have had the opportunity to discuss the purposes
and possible risks of this testing with my doctor or someone
my doctor has designated. I know that genetic counseling is
available to me before and after the testing.’’ An IC from
Women’s Health Partners, LLC (an obstetrics and gynecology
practice in Florida, US) included the following statements:
Genetic counseling is recommended to all pregnant
women who will be 35 years old or older at delivery and is
available to all pregnant women. . . . Genetic Coun-seling
with a certified genetic counselor is available to all
patients at Women’s Health Partners. Please discuss these
options with your physician or midwife.
The cost to the patient (if any) of either pre- or post-test
counseling was not mentioned in any IC. Over half of all IC
recommended or suggested post-test genetic counseling (as
noted above), but few mentioned psychosocial consid-erations
or other supports. For example, two IC mentioned that
prenatal screening can cause anxiety for patients, and two IC
mentioned that patients may make termination deci-sions
based on the results of screening and testing. Only one IC
mentioned any support groups that are available for families
affected by a genetic condition.
Information about other test considerations
Although over one-third of IC (n = 13) indicated that the
patient was responsible for the cost of cfDNA screening
(either through insurance or out-of-pocket), only five IC (as
noted above) listed the cost of the test (Table 4). Over half of
IC (n = 18) explained test procedures involving the patient,
which consist solely of a blood draw (and, in case of assay
failure, a second blood draw). As noted above, many IC dis-
cussed sample retention; however, less than one-third of IC (n
= 9) disclosed that the patient ’s health care provider may
share information about her pregnancy outcome with the
testing laboratory (commonly done for evaluating test per-
formance). While (as noted above) IC frequently
mentioned
Informed decision-making about prenatal cfDNA screening
regulatory approval of laboratory facilities (e.g., Clinical
Laboratory Improvement Amendment [CLIA] validation in the
US), only three IC mentioned whether the test was sub-ject to
and/or had received regulatory approval; all of these
referenced the fact that cfDNA screening has not received
approval from the US Food & Drug Administration (although
such approval is not currently required) (Table 4).
Discussion
This analysis of 32 IC revealed a wide range in the quantity
and quality of information offered to women at the time of
their decision-making about cfDNA screening. Commer-cial IC
and Non-Commercial IC differed most strikingly in their length
and reading difficulty, which appeared to stem from a greater
tendency among Commercial IC to combine legal disclosures,
financial responsibility statements, and informed consent
information into one document. Such doc-uments contained a
great deal of useful information, but were sometimes visually
crowded and linguistically com-plex. Readability of IC is
crucial if these documents are to be useful for women making
decisions about prenatal screening; in the US, for example,
over three-quarters of women of childbearing age do not have
a college degree, and education levels vary greatly between
populations from different backgrounds [46]. Indeed, US
federal guidelines for labeling of medical devices specify that
information directed at patients should be at an eighth-grade
reading level or below [47]. We suggest that readability of IC
was also compromised by combining IC with laboratory order
forms, examples of which we found in both Commercial and
Non-Commercial IC. Such forms often crowded clinician- and
patient-directed information together into a single sheet,
using small fonts and very little empty space. Information and
questions directed at clinicians, such as medical billing codes
and clinical indications for testing, contain jargon and
abbreviations that may confuse patients, and interspersing
these elements with information directed at patients can
further confound efforts to communicate clearly and facili-
tate informed decision-making.
Information about the test itself varied greatly within our
sample set of IC. For example, while most IC recommended
confirmatory diagnostic testing for screen-positive results and
some IC strongly emphasized that cfDNA screening is not
diagnostic, nearly a quarter of IC never used the phrases ‘‘not
diagnostic,’’ ‘‘screen,’’ or ‘‘screening test’’ to describe
cfDNA screening. Explanations that cfDNA is not diagnostic are
particularly important, given reports that many women
misunderstand cfDNA screening results to be diagnostic and
may even terminate without confirmatory testing [37,48].
Such misunderstandings might also be lessened by clear
expectations regarding screening results, but many IC in our
sample did not explain how results would be presented, to
whom they would be provided, and/or that results can be
incorrect. The high test sensitivity of cfDNA screening was
often cited by IC in our sample (most often mentioned was
the ≥ 99% sensitivity for trisomy 21 in high-risk pregnancies);
but to understand the chance that an actual screening result
will be correct, sensitivity is less helpful than positive and
negative predictive value (PPV and NPV) —– which were not
mentioned in any IC in our sample.
369
In addition, only a few IC discussed genetic information
that cfDNA screening can reveal about a parent,
information that may take many patients by surprise. Many
patients and clinicians alike were surprised to hear news
reports that cfDNA screening may reveal tumors or cancer
in the pregnant woman, information that was not included
in any IC in our sample; though these reports were
published after the documents in our sample were
collected, multiple laboratories had for some time been
aware of this capability and were collecting data (and
sometimes returning infor-mation to clinicians) about this
phenomenon [49]. Overall, though many IC mentioned the
benefits of cfDNA screening, few discussed these
informational risks, and information about psychosocial
issues —– such as anxiety or termination decision-making
—– was notably absent from nearly all IC.
Finally, information about screened conditions was sparse
in our sample and rarely included information about pheno-
types, variability, or quality of life. While truly complete
information about screened conditions is impractical and
likely unnecessary in pre-test decision-making, even brief
descriptions of screened conditions may provide contextual
information that conveys information beyond descriptions of
genetic mutations and helps patients understand the diversity
of conditions being screened. One way to offer interested
patients more information without overwhelming others is to
list other resources; however, although many IC included links
to company or clinic websites with more infor-mation (which
we did not assess in this study), only one IC listed any patient
support organizations for genetic condi-tions —– resources
that many families value for the depth and relevance of
condition-specific information they can provide [33,50].
Based on our findings, along with prior recommendations
for clinical informed consent and best practices for cfDNA
screening, below we offer recommendations for facilitating
informed decision-making for cfDNA screening with written
informed consent documents.
Recommendations
Informed consent should be sought before performing
cfDNA screening, and should be preceded by pretest
counseling. Written informed consent is a good option, but
written and/or signed documents do not eliminate the
need for ver-bal counseling.
Informed consent documents should be visually
separate from laboratory order forms, legal agreements,
and financial responsibility statements, and should include
a copy that the patient can take home.
Informed consent documents should be easy to read. Plain
language should be used preferably written at a 9th grade
reading level or below in the patient’s native lan-guage. Type
size should be large enough for ease of reading, with plenty of
‘‘white space’’ on the page, and text should never or very
rarely be in all-capital letters or italics.
Informed consent documents should clearly state the
benefits and risks of cfDNA screening, including unexpected
findings, psychosocial considerations, and the potential for
decision-making about pregnancy continuation and/or
management. Alternatives to cfDNA screening should be
370
presented, including the option to decline all prenatal
screening/testing for fetal conditions.
Any clinical indications for offering cfDNA screening
(e.g., elevated risk from prior screening), along with test
cost and/or coverage considerations, should be explained
verbally and/or in writing.
Informed consent documents should clearly state that
cfDNA is not diagnostic, that there can be false positives,
errors, and assay failures, and that any screen-positive
results should be confirmed with diagnostic testing. Statis-
tics regarding the test, if given, should include false-
positive rates, positive predictive values, or other
numerical indica-tors that clarify how often screening
results are correct or incorrect.
Informed consent documents should recommend
genetic counseling for screen-positive results, and the
availability (and potential cost) of pre-test and post-test
genetic coun-seling for any patient should be disclosed.
Informed consent documents should list all conditions
being screened, and should include a brief, family-
relevant explanation of the conditions (e.g., possible
phenotypes, quality of life) and variability within and
between them. Identifying patient support organizations
for screened con-ditions is also helpful, if space allows.
Regardless of whether a signature is required, informed
consent documents should include a simple consent state-
ment, not combined with legal or financial agreements.
Also prominently listed should be the name and contact
informa-tion of a local clinical provider who is available
for further questions.
Limitations
Documents were collected for this analysis during a limited
time period ending in December 2014. Due to the rapid
changes in cfDNA screening tests and in professional rec-
ommendations for offering cfDNA screening, IC offered by any
particular laboratory or clinic may have changed since our
sample set was collected. While every effort was made to
represent the range of IC available to patients, this sam-ple is
not comprehensive; nor is it weighted to represent
proportionate audiences for particular documents, as we did
not have data to support such weighting. For exam-ple,
documents used only by one clinical practice were not
weighted differently than documents distributed by a
commercial laboratory for use by many clinics. Many doc-
uments in our coding set included links or references to
websites, online pamphlets, or other educational materials,
while others may be physically distributed with additional
printed materials; as assessing the availability and distri-
bution of these additional materials was beyond the scope of
this study, such other materials were not sought out or
analyzed. Finally, this analysis cannot assess the content or
impact of verbal counseling or other decisional support that
patients may receive before choosing or refusing cfDNA
screening, or after receiving results. We emphatically affirm
the value of such counseling and support, and recognize that
informed decision-making is a process that is documented —
– but never fully encapsulated —– in reading and signing a
form.
M. Michie et al.
Conclusion
The availability of informed consent documentation from
many health care providers and commercial laboratories
points toward progress in assuring informed decision-making
regarding cfDNA screening. However, the variable quality of
these documents suggests the need for informed con-sent
guidelines to support laboratories and clinics. Toward this
end, we have offered recommendations for written materials
to guide and document informed consent before performing
cfDNA screening. In combination with verbal counseling by a
health care provider, informed consent doc-uments that
follow these recommendations can help ensure that pregnant
women and their families have the opportu-nity to make
informed, values-appropriate decisions about cfDNA
screening.
Funding
This study was supported by the following funding sources:
NIH grant # R00HG006452 (MM and RR); NIH grant #
P50HG003389 (SAK); and NIH grant # P50HG003391 (MAM).
Disclosure of interest
The authors declare that they have no competing interest.
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